Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
The discovery and implementation of antibiotic drugs nearly 70 years ago revolutionized human medicine. Just a short time ago infectious diseases were the number one killer of Americans. Largely because of antibiotic development, infectious disease is no longer the leading cause of death in the U.S. and the average life expectancy has increased by nearly 30 years. The spectacular advancement of antibiotics from the mid-1940's to 1961 lead the U.S. Surgeon General to proclaim before Congress in 1969 that it is “time to close the book on infectious disease as a major health threat.” In the decades that followed, it was found that heavy antibiotic use had resulted in an alarming increase in bacterial resistance (Talbot et al. (2006) Clin. Infect. Dis., 42:657-668). In parallel to the increase in resistance, major pharmaceutical companies abandoned antibiotic discovery in favor of life style and chronic disease drugs that offer larger profit margins. Consequently, only two novel classes of antibiotics have been introduced in the past 35 years. In 2004, the Infectious Disease Society of America released a report that a public health crisis is brewing as antibiotic research stagnates. Statics support this claim: (i) 70% of hospital acquired infection are resistant to at least one major class of antibiotics; (ii) 2 million patients acquire hospital bacterial infections per year resulting in >90,000 deaths, a number that has increase 6-fold since 1992, (iii) drug resistant infections cost the U.S. economy $5 billion annually, and (iv) a number of pathogens, such as methicillin resistance Staphylococcus aureus (MRSA) which represents 70% of S. aureus hospital acquired infections, are multidrug resistant and difficult to treat with existing antibiotics. Because of these factors there is an urgent need to discover and develop new antibiotics that work by novel mechanism (Talbot et al. (2006) Clin. Infect. Dis., 42:657-668; Norrby et al. (2005) Lancet Infect. Dis., 5:115-119; Payne, D. J. (2008) Science 321:1644-1645).
Natural products (NPs), which are by far the leading source of antibiotics, are developmentally hindered by low fermentation yields and structural complexity that make synthesis and optimization difficult (Walsh, C. (2003) Nat. Rev. Microbiol., 1:65-70; Baltz, R. (2007) Microbe 2:125-131; Demain et al. (2008) Prog. Drug Res., 65:251,253-289). For these and other reasons, pharmaceutical companies have largely abandoned NPs and developing new antibiotics (Walsh, C. (2003) Nat. Rev. Microbiol., 1:65-70; Baltz, R. (2007) Microbe 2:125-131; Baltz, R. H. (2008) Curr. Opin. Pharmacol., 8:557-563; Overbye et al. (2005) Drug Discov. Today 10:45-52; Nathan et al. (2005) Nat. Rev. Drug Discov., 4:887-891). Even with the advent of robotics and high-throughput technology, laborious screens used by pharmaceutical industries are still limited in their ability to process tens to hundreds of thousands of mutants (Demain et al. (2008) Prog. Drug Res., 65:251,253-289; Baltz, R. H. (2001) Antonie Van Leeuwenhoek, 79:251-259). To date, predation has not been utilized for natural product optimization, in part, because the major natural product producers (actinomycetes) are not predatory bacteria.